The term “cancer” generally refers to any of a group of more than 100 diseases caused by the uncontrolled growth of abnormal cells. Cancer can take the form of solid tumors and lymphomas, and non-solid cancers such as leukemia. Unlike normal cells, which reproduce until maturation and then only as necessary to replace wounded cells, cancer cells can grow and divide endlessly, crowding out nearby cells and eventually spreading to other parts of the body.
The principal problem of cancer chemotherapy is achieving good therapeutic indices for the compounds administered to kill the tumor cells. In general, drugs and radiation used to kill cancer cells are also toxic to cells of normal tissue, and so side effects are often severe. The majority of drug-mediated cancer therapies rely on drugs that selectively poison dividing cells. These drugs can be effective, because cancer cells generally divide more frequently than normal cells. Unfortunately, however, there are exceptions to this rule in most cancers, which means that such drugs almost inevitably are unable to kill all cells in a tumor. Moreover, even for drugs that act on mechanisms specific to cancer cells, there are, in the majority of patients, cancer cells not killed by administration of the drug.
While specific proteins can confer drug resistance to a cancer cell, such as the proteins responsible for the multiple drug resistance (“MDR”) phenotype, the very nature of the tumor formed by solid cancers, particularly its vascular architecture, contributes significantly to the ability of the cancer to survive drug therapy. As a tumor grows, it requires a blood supply and the growth of new vasculature. The new vasculature that supports the tumor growth is, not surprisingly given the uncontrolled growth that characterizes most cancers, highly disordered, leaving significant portions of the tumor under-vascularized, and the vascularized portions of the tumor subject to intermittent blockage. Because the vasculature delivers oxygen (and chemotherapeutic agents) to cells, tumors therefore typically contain “hypoxic” regions, regions in which the oxygen concentration is significantly lower than in the vast majority of normal tissues and where there may be poor delivery of chemotherapeutic agents.
Oxygen is critical in the supply of energy to a cell in the form of ATP produced by mitochondrial action. A cell's only other source of ATP in the amounts needed to support the cell is from anaerobic glycolysis. Given the demand for ATP in cell division and the hypoxic nature of tumors, it is therefore not surprising that many cancers exhibit, relative to normal cells, increased glycolysis. This attribute of cancer cells was described in the reference Dickens, 1943, Cancer Research 3:73, which reported “the typical intact cancer cell exhibits an unusual ability to utilize glucose by the process of anaerobic glycolysis through lactate”.
Given the increased glycolysis in cancer cells relative to normal cells, scientists questioned whether inhibition of anaerobic glycolysis by metabolic poisons would preferentially target cancer cells. The compound 2-deoxy-D-glucose (also known and referred to herein as 2-deoxyglucose and 2-DG) is such a metabolic poison. 2-DG inhibits glycolysis in cancer cells, as reported in the reference Woodward, 1954, Cancer Res. 14:599–605. However, while many cell-based and animal studies of 2-DG as an anti-cancer agent have been conducted, both as a single agent and in combination with other anti-cancer drugs and/or radiation, the compound has not been approved by any regulatory agency for use in the treatment of cancer. See Yamada, 1999, Cancer Chemother. Pharmacol. 44(1):59–64; Reinhold, September 2000, Oncol. Rep., 7(5):1093–97; Mese, March 2001, Anticancer Res. 21:1029–33; Lampidis, 2 Mar. 2001, PCT WO 01/82926, Yeung, 11 Dec. 2001, PCT WO 02/58741; and Pitha, Mar. 21, 2002, U.S. patent publication No. 20020035071.
There could be a significant therapeutic benefit from cytotoxic compounds that preferentially target cancer cells based on increased glycolysis. Because cancer cells are known to have, relative to normal cells, increased production of glucose transporters, including GLUT1 and GLUT3, one could attempt to target glucose transport in cancer chemotherapy. While a number of known anti-cancer agents have a structure that can be described as a glucose moiety attached to a cytotoxic agent, and so might be substrates for GLUT1 and/or GLUT3, none of these agents has been widely used with great success to treat cancer.
One such compound, the naturally occurring compound streptozotocin [2-deoxy-2-(3-methyl-3-nitroso-ureido)-D-glucose] is an antibiotic and anti-mitotic compound produced by Streptomyces achromogenes (see also U.S. Pat. No. 3,694,428). In streptozotocin, a cytotoxic N-nitroso urea group is attached to the 2 position of glucosamine. The compound is relatively unstable in that the cytotoxic moiety is readily released from the compound in the presence of water. The compound appears to be transported into cells by the glucose transporter GLUT2, which may account for its toxicity to pancreatic islet cells. A limited number of streptozotocin analogs have also been prepared (see U.S. Pat. No. 3,940,383). However, neither streptozotocin nor its analogs has found any significant use in anti-cancer therapies.
Glufosfamide (beta-D-glucosyl-ifosfamide mustard) is another anti-cancer agent that can be described as a cytotoxic agent linked to a glucose moiety. This compound contains the cytotoxic agent ifosfamide coupled to glucose via an ester linkage at the oxygen atom at the 1-position of glucose (see U.S. Pat. No. 5,622,936). The compound has been described as having been made in an effort to target the tumor's need for energy as a means to enhance uptake of ifosfamide into cancer cells (see the website of the dkfz, 14 Jan. 2003, www.toxea.de). The compound has been reported to be subject to cell surface glucose transport, via the SAAT1 receptor. Like streptozotocin, however, glufosfamide is relatively unstable, both chemically and enzymatically, ensuring that ifosfamide will be cleaved from the glucose after administration. Such cleavage could take place in the plasma, by the action of serum esterases, or in the cell, allowing the ifosfamide potentially to diffuse from the cell, which in either event could lead to increased toxicity and/or decreased efficacy.
The glyco-S-nitrosothiols are likewise relatively unstable compounds that can be described as cytotoxic agents linked to sugars. These compounds have been described as targeting tumor cells that over-express GLUT1 preferentially (see Ramirez et al., 1996, Bioorg. Med. Chem. Lett. 6(21): 2575–2580; and Cantuaria et al., 15 Jan. 2000, Cancer 88(2): 381–388). One glyco-S-nitrosothiol called 2gluSNAP has a structure in which a nitric oxide donating cytotoxic moiety (S-nitroso-N-acetyl-penicillamine) is linked to 2-deoxyglucosamine at the 2 position via an amide bond. The resulting compound is unstable, which can result in release of the cytotoxic nitric oxide before entry into the targeted cell or diffusion out of the targeted cell.
Compounds characterized as single photon-emitting radiotracers that contain a glucose moiety linked to a single photon-emitting moiety via a heterocyclic, hydrocarbon, or aromatic group have been described as allegedly useful for the diagnosis and treatment of cancer (see PCT publication No. WO 99/20316). These compounds include, for example, 2-O-(3′-iodobenzyl)-D-glucose and N-(4′-iodobenzyl)-D-glucosamine.
Compounds characterized as prodrug forms of pharmacologically active substances, including anti-cancer agents, and that contain a glucose or other sugar moiety linked to a pharmacologically active agent at the 1 position either directly or through a self-immolative spacer have been described (see U.S. Pat. No. 5,621,002) as substrates for human glycosidases without indication of whether the glucose moiety contributed to the specificity of the prodrug for a cancer cell.
Thus, while compounds have been made that contain a cytotoxic agent linked to glucose, most of those compounds have not been approved for the treatment of cancer, and none of those compounds appears to have significant specificity for cancer cells. There remains a need for methods and compositions for treating cancer, including tumors, non-solid cancers, and cancer cells, that are widely applicable in a variety of cancers. The present invention provides such methods, as well as compounds and compositions useful in those methods.